WO2017080358A1 - 用于聚合酶链式反应的检测机构及聚合酶链式反应装置 - Google Patents

用于聚合酶链式反应的检测机构及聚合酶链式反应装置 Download PDF

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Publication number
WO2017080358A1
WO2017080358A1 PCT/CN2016/103153 CN2016103153W WO2017080358A1 WO 2017080358 A1 WO2017080358 A1 WO 2017080358A1 CN 2016103153 W CN2016103153 W CN 2016103153W WO 2017080358 A1 WO2017080358 A1 WO 2017080358A1
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Prior art keywords
excitation
subunit
heating
module
polymerase chain
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English (en)
French (fr)
Inventor
邱宪波
叶祥忠
葛胜祥
张师音
高鹏飞
吉尚志
阳勇良
邱子欣
夏宁邵
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Beijing University of Chemical Technology
Xiamen University
Beijing WanTai Biological Pharmacy Enterprise Co Ltd
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Beijing University of Chemical Technology
Xiamen University
Beijing WanTai Biological Pharmacy Enterprise Co Ltd
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Application filed by Beijing University of Chemical Technology, Xiamen University, Beijing WanTai Biological Pharmacy Enterprise Co Ltd filed Critical Beijing University of Chemical Technology
Priority to US15/774,953 priority Critical patent/US10864521B2/en
Priority to KR1020187013162A priority patent/KR102246869B1/ko
Publication of WO2017080358A1 publication Critical patent/WO2017080358A1/zh
Anticipated expiration legal-status Critical
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    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
    • G01N21/64—Fluorescence; Phosphorescence
    • G01N21/645—Specially adapted constructive features of fluorimeters
    • G01N21/6452—Individual samples arranged in a regular 2D-array, e.g. multiwell plates
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
    • G01N21/64—Fluorescence; Phosphorescence
    • G01N21/645—Specially adapted constructive features of fluorimeters
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
    • G01N21/64—Fluorescence; Phosphorescence
    • G01N21/6402—Atomic fluorescence; Laser induced fluorescence
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L7/00—Heating or cooling apparatus; Heat insulating devices
    • B01L7/52—Heating or cooling apparatus; Heat insulating devices with provision for submitting samples to a predetermined sequence of different temperatures, e.g. for treating nucleic acid samples
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L7/00—Heating or cooling apparatus; Heat insulating devices
    • B01L7/52—Heating or cooling apparatus; Heat insulating devices with provision for submitting samples to a predetermined sequence of different temperatures, e.g. for treating nucleic acid samples
    • B01L7/525—Heating or cooling apparatus; Heat insulating devices with provision for submitting samples to a predetermined sequence of different temperatures, e.g. for treating nucleic acid samples with physical movement of samples between temperature zones
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
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    • G—PHYSICS
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    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
    • G01N21/64—Fluorescence; Phosphorescence
    • G01N21/6428—Measuring fluorescence of fluorescent products of reactions or of fluorochrome labelled reactive substances, e.g. measuring quenching effects, using measuring "optrodes"
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    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/573—Immunoassay; Biospecific binding assay; Materials therefor for enzymes or isoenzymes
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/14—Process control and prevention of errors
    • B01L2200/143—Quality control, feedback systems
    • B01L2200/147—Employing temperature sensors
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/18—Means for temperature control
    • B01L2300/1805—Conductive heating, heat from thermostatted solids is conducted to receptacles, e.g. heating plates, blocks
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2400/00—Moving or stopping fluids
    • B01L2400/04—Moving fluids with specific forces or mechanical means
    • B01L2400/0403—Moving fluids with specific forces or mechanical means specific forces
    • B01L2400/0442—Moving fluids with specific forces or mechanical means specific forces thermal energy, e.g. vaporisation, bubble jet
    • B01L2400/0445—Natural or forced convection
    • G—PHYSICS
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    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
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    • G01N2021/6417—Spectrofluorimetric devices
    • G01N2021/6419—Excitation at two or more wavelengths
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    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
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    • G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
    • G01N21/64—Fluorescence; Phosphorescence
    • G01N2021/6417—Spectrofluorimetric devices
    • G01N2021/6421—Measuring at two or more wavelengths
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
    • G01N21/64—Fluorescence; Phosphorescence
    • G01N21/645—Specially adapted constructive features of fluorimeters
    • G01N2021/6463—Optics
    • G01N2021/6471—Special filters, filter wheel
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
    • G01N21/64—Fluorescence; Phosphorescence
    • G01N21/645—Specially adapted constructive features of fluorimeters
    • G01N2021/6484—Optical fibres
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
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    • G01N2201/06—Illumination; Optics
    • G01N2201/062—LED's
    • G01N2201/0627—Use of several LED's for spectral resolution
    • G—PHYSICS
    • G01—MEASURING; TESTING
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    • G01N2201/08—Optical fibres; light guides
    • G—PHYSICS
    • G01—MEASURING; TESTING
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
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    • G01N2201/0833—Fibre array at detector, resolving
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
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Definitions

  • the invention relates to the field of biomedical engineering technology, in particular to a detection mechanism for polymerase chain reaction and a polymerase chain reaction device.
  • PCR Polymerase Chain Reaction
  • PCR is a periodic gene amplification reaction.
  • Each amplification cycle includes three stages of DNA denaturation, annealing and extension, and each stage requires different temperature conditions. The three stages constitute a complete thermal cycle.
  • the periodic reaction temperature conditions required for PCR are often provided by a professional PCR gene amplification instrument.
  • the PCR gene amplification instrument is provided by a complex software and hardware design and switches the three reaction temperatures required for PCR in real time. During the process of switching between different reaction temperatures, the transition time between different reaction stages often takes a long time, which limits the PCR reaction time to 1.5 to 2.5 hours.
  • convection PCR relies on one or two constant reaction temperatures to establish a stable temperature gradient across the reaction tube. Based on the thermodynamics principle, a periodic motion flow field is generated in the reaction tube. The amplified sample is reciprocated between the ends of the tube at different temperatures, thereby obtaining the temperature conditions required for PCR amplification.
  • the existing convection PCR reaction device still has many shortcomings, such as the inability to realize multi-wavelength real-time detection of the fluorescence signal during sample amplification, and cannot support the on-demand operation mode, which seriously affects the control time. , so that the total time consumption of PCR amplification technology can not be reduced to the desired range; Secondly, the temperature control mode is single, the amplification reaction is susceptible to the external environment temperature, and the detection process has low flexibility; in addition, the detection device has many devices, complicated structure and high detection cost.
  • the object of the present invention is to propose a detection mechanism for polymerase chain reaction and a polymerase chain reaction device to realize a polymerase chain reaction and perform real-time detection of a fluorescent signal in an amplification reaction.
  • the present invention provides a detection mechanism for polymerase chain reaction, comprising:
  • each of the excitation module groups includes two excitation modules, the excitation module group capable of providing excitation light of two wavelengths;
  • Exciting an optical fiber connected to the excitation module group, the excitation fiber capable of transmitting the excitation light to at least one reaction tube, each of the reaction tubes receiving excitation light of two wavelengths;
  • At least one receiving module group connected to the receiving fiber, each of the receiving module groups including two receiving modules to respectively receive the fluorescent signals of two wavelengths from the same reaction tube, and Converting the fluorescent signal into an electrical signal output;
  • the detecting mechanism detects the reaction tube in a time-sharing manner, and multiplexes the receiving module group to obtain an output result.
  • each of the excitation modules includes an excitation light source and a forward optical unit, and the excitation light source transmits the excitation light to the excitation fiber via the forward optical unit, and each of the excitation light sources can provide a The excitation light of the wavelength is transmitted to the reaction tube through the excitation fiber.
  • the forward optical unit includes a lens and an excitation filter, the lens being located on a side close to the excitation light source.
  • each of the receiving modules includes a rearward optical unit for transmitting the fluorescent signal to the photosensor, and a photosensor for using the fluorescent signal Converted to electrical signal output.
  • the rearward optical unit includes a focus lens and a receiving filter, the focusing lens being located on a side close to the receiving fiber.
  • excitation fiber and its corresponding receiving fiber form a 90 degree optical angle with each other.
  • the present invention also provides a polymerase chain reaction apparatus comprising the above-described detection mechanism for polymerase chain reaction.
  • the utility model also includes a host computer human interaction subsystem, a lower computer control subsystem, a heating module and a shading module, wherein:
  • the upper computer human-computer interaction subsystem is connected with the lower computer control subsystem data, and the upper computer human-computer interaction subsystem is configured to provide a human-computer interaction interface and receive an input instruction of the operator;
  • the lower computer control subsystem is configured to control a temperature of the heating module according to an input instruction received by the upper computer human-machine interaction subsystem;
  • the heating module is capable of providing a corresponding heating temperature for achieving a convective polymerase chain reaction
  • the light shielding module is configured to block light entering the reaction tube.
  • the light shielding module includes an upper light shielding cover and a lower light shielding door
  • the upper light shielding cover is for shielding external visible light
  • the lower light shielding door includes an elastic member, and the elastic member can enable the lower light shielding door to be in a normal condition.
  • the lower state is a closed state; the lower light-shielding door can block visible light from entering the reaction tube during insertion of the reaction tube into the reaction well.
  • the heating module includes a high temperature heating subunit, a low temperature heating subunit, and a thermal insulation subunit, wherein the high temperature heating subunit, the low temperature heating subunit, and a central portion of the thermal insulation subunit are capable of forming a reaction a hole position for inserting the reaction tube, the high temperature heating subunit is located below the low temperature heating subunit, the insulation subunit is located between the high temperature heating subunit and the low temperature heating subunit, The low temperature heating subunit is prevented from absorbing the radiant heat of the high temperature heating subunit.
  • the high temperature heating subunit includes a lower layer heating rubber and a lower layer heat conducting module, the lower layer heating rubber is located at a side of the lower layer heat conducting module, and the lower layer heat conducting module is capable of transmitting heat generated by the lower layer heating rubber to the The lower part of the reaction tube;
  • the low temperature heating subunit includes an upper layer heating rubber, an upper layer heat conducting module, the upper layer heating rubber is located at a side of the upper layer heat conducting module, and the upper layer heat conducting module is capable of transferring heat generated by the upper layer heating rubber to the reaction tube The upper part.
  • the high temperature heating subunit further includes a lower layer temperature measuring sensor connected to the lower computer control subsystem, configured to convert the measured heating temperature of the high temperature heating subunit into an electrical signal and feed back to the Lower computer control subsystem;
  • the low temperature heating subunit further includes an upper temperature measuring sensor connected to the lower computer control subsystem, configured to convert the measured heating temperature of the low temperature heating subunit into an electrical signal and feedback to the lower computer control in real time.
  • the lower computer control subsystem is capable of receiving temperature signals of the lower layer temperature sensor and the upper layer temperature sensor, and is set according to the temperature signal and an input command received by the host computer interaction subsystem The difference between the temperatures adjusts the heating temperature of the heating module.
  • the detecting mechanism of the present invention is provided with at least one excitation module group, each excitation module group includes two excitation modules, the at least two excitation modules can provide excitation light of two wavelengths, and the excitation fiber will have two wavelengths.
  • the excitation light is transmitted to the corresponding reaction tubes, each of which receives the excitation light of two wavelengths, and the fluorescent dye in the reaction tube is irradiated by the excitation light to emit a fluorescent signal, and then transmitted to the at least one receiving module group via the receiving optical fiber.
  • Each receiving module group receives two wavelengths of fluorescent signals from the same reaction tube and converts them into electrical signal outputs.
  • the detecting mechanism can adopt dual-wavelength detection. Regardless of the number of the excitation module and the reaction tube, the simultaneous detection of multiple reaction tubes can be completed by using at least one receiving module group through the principle of time division multiplexing.
  • the time division refers to the time-series detection of two or more reaction tubes; the multiplexing means that the plurality of reaction tubes can share the receiving module group at different times, so that the receiving module group can be realized.
  • the detection mechanism can allow multiple reaction tube cycle detection, to achieve The real-time detection of the fluorescent signal, along with the inspection, shortens the detection time.
  • Figure 1 is a schematic view showing the structure of an embodiment of a detection mechanism for polymerase chain reaction of the present invention.
  • FIG. 2 is a schematic view showing the structure of an embodiment of the polymerase chain reaction device of the present invention.
  • Figure 3 is a diagram showing the structure of an independent reaction well position in an embodiment of the polymerase chain reaction device of the present invention schematic diagram.
  • FIG. 4 is a schematic view showing the structure of a heating module in one embodiment of the polymerase chain reaction device of the present invention.
  • the detection mechanism 3 for the polymerase chain reaction comprises:
  • each of the excitation module groups includes two excitation modules 31, the excitation module group capable of providing excitation light of two wavelengths;
  • An excitation fiber 32 is coupled to the excitation module group, and the excitation fiber 32 is capable of transmitting the excitation light to at least one reaction tube 5, each of the reaction tubes 5 receiving excitation light of two wavelengths;
  • At least one receiving module group connected to the receiving optical fiber 33, each of the receiving module groups including two receiving modules 34 for respectively receiving the fluorescent signals of two wavelengths from the same reaction tube 5, and Converting the fluorescent signal into an electrical signal output;
  • the detecting mechanism 3 detects the reaction tube in a time-sharing manner and multiplexes the receiving module group Get the output.
  • the detecting mechanism is provided with at least one excitation module group, each excitation module group includes two excitation modules, the at least two excitation modules can provide excitation light of two wavelengths, and the excitation fiber transmits the excitation light of two wavelengths to the corresponding
  • the reaction tubes each receive excitation light of two wavelengths, and the fluorescent dye in the reaction tube is irradiated by the excitation light to emit a fluorescent signal, and then transmitted to the at least one receiving module group via the receiving optical fiber, each receiving module group receiving from Fluorescent signals of two wavelengths in the same reaction tube are converted into electrical signal outputs.
  • the detecting mechanism can adopt dual-wavelength detection. Regardless of the number of the excitation module and the reaction tube, the simultaneous detection of multiple reaction tubes can be completed by using at least one receiving module group through the principle of time division multiplexing.
  • the time division refers to the time-series detection of two or more reaction tubes; the multiplexing means that the plurality of reaction tubes can share the receiving module group at different times, so that the receiving module group can be realized.
  • the detection mechanism can allow multiple reaction tube cycle detection, to achieve The real-time detection of the fluorescent signal, along with the inspection, shortens the detection time.
  • the excitation light of the two wavelengths provided by each excitation module group may be different, that is, two or more wavelengths may be used, thereby achieving the same reaction hole position.
  • the reaction tube on the above was subjected to multi-wavelength detection.
  • each of the excitation modules 31 includes an excitation light source 311 and a forward optical unit 312 via the forward optical.
  • the unit 312 transmits the excitation light to the excitation fiber 32, and each of the excitation light sources 311 can provide excitation light of one wavelength and is respectively transmitted to the reaction tube 5 through the excitation fiber 32.
  • the excitation light source 311 can be selected as a light emitting diode (LED light source), which has small volume, low voltage, long service life, and low cost.
  • the excitation light is arranged by a plurality of LED light sources, and the LED light source in the entire column is allowed to have a plurality of different wavelengths, and is transmitted to the reaction holes of the plurality of reaction tubes 5 by a plurality of excitation fibers 32 distributed in parallel.
  • the forward optical unit 312 can include a lens and an excitation filter, the lens being located The lens is closer to the excitation light source 311 than to the side of the excitation light source 311, that is, compared to the excitation filter.
  • the lens has a function of collecting light, and the excitation filter is capable of selecting excitation light of a specific wavelength.
  • each of the receiving modules 34 includes a backward optical unit 341 and a photo sensor 342, and the backward optical unit 341 is used.
  • the fluorescent signal is transmitted to the photosensor 342, which is used to convert the fluorescent signal into an electrical signal output.
  • the photosensor 342 can be a photodiode, which has good linearity, high sensitivity, low noise, low price, small size, and long service life.
  • the plurality of photodiodes can form a whole array of photosensors, receive the fluorescent signals from the plurality of reaction holes through a plurality of parallel receiving optical fibers 33, and then convert the collected fluorescent signals into electrical signals and transmit them to the lower computer control subsystem 2 , by which to carry out the next signal and data processing.
  • the rearward optical unit 341 includes a focus lens that is located on a side close to the receiving fiber 33, and a receiving lens that is closer to the receiving fiber 33 than the receiving filter. To achieve better reception through the focus lens.
  • the excitation fiber 32 and its corresponding receiving fiber 33 form an optical angle of 90 degrees with each other.
  • the excitation fiber 32 and the corresponding receiving fiber 33 may also be at other angles.
  • the present invention also proposes a polymerase chain reaction apparatus comprising the detection mechanism 3 for polymerase chain reaction described in each of the above embodiments.
  • the polymerase chain reaction device may further include a host computer human interaction subsystem 1, a lower computer control subsystem 2, a heating module 4, and a shading module 6, wherein:
  • the host computer human-computer interaction subsystem 1 and the lower computer control subsystem 2 are connected in data, that is, the upper computer human-computer interaction subsystem 1 and the lower-level machine control subsystem 2 are connected to each other and realize data exchange.
  • the upper computer human-computer interaction subsystem 1 is used for providing a human-computer interaction interface, and receiving input instructions from an operator, and can also analyze and process data;
  • the lower computer control subsystem 2 is configured to control the temperature of the heating module 4 according to an input instruction received by the upper computer human-machine interaction subsystem 1;
  • the heating module 4 can provide a corresponding heating temperature for implementing a convective polymerase chain reaction
  • the light shielding module 6 is used to block light entering the reaction tube 5, where the light mainly refers to light in the external environment.
  • the upper computer human-computer interaction subsystem 1 can be provided with an independent processor and a touch screen.
  • a friendly human-computer interaction operation interface is provided, and the operation of the lower computer control subsystem 2 is controlled according to the user input instruction.
  • the detection result and the data file can be analyzed and managed;
  • the lower machine control subsystem 2 is used to control the temperature of the heating module 4, and provides a stable reaction temperature for CPCR (convection polymerase chain reaction) isothermal amplification;
  • the upper computer Data communication between the machine interaction subsystem 1 and the lower computer control subsystem 2 can be performed through a serial interface or a USB interface.
  • the detecting mechanism 3 cooperates with the lower computer control subsystem 2 to realize real-time collection of fluorescence detection signals during CPCR isothermal amplification.
  • the lower computer control subsystem 2 can output a control signal to the heating module 4 to ensure a desired reaction temperature, and can also cooperate with the detecting mechanism to realize multi-wavelength fluorescence detection.
  • the shading module 6 can be configured with an independent shading sub-unit for each detecting hole position, overcoming the mutual influence between the detecting hole positions, and supports both batch detection and on-demand inspection.
  • the light shielding module 6 includes an upper light shielding cover 61 for shielding visible light in an external environment, and a lower light shielding cover 62 including an elastic member, the elastic The member can cause the lower shutter door 62 to be in a normally closed state; the lower shutter door 62 can block visible light from entering the reaction tube 5 during insertion of the reaction tube 5 into the reaction hole position.
  • the upper light shielding cover 61 can block visible light from the external environment of the device.
  • the lower shutter 62 includes an elastic member, that is, the lower shutter 62 is a spring door, and the lower shutter 62 is always closed unless inserted into the reaction tube 5 due to the pulling force of the spring force, so that it can block visible light inside the instrument. Entering the detection hole position, more importantly, after the upper light-shielding cover 61 is opened, before the insertion reaction tube 5 or during the insertion process, the lower light-shielding door 62 can block visible light that may enter the detection hole position, which effectively overcomes the follow-up In the inspection mode, the mutual interference and influence between the hole positions are detected.
  • the heating module 4 needs to provide the reaction temperature conditions required for convective amplification.
  • the heating module 4 includes a high temperature heating subunit 42, a low temperature heating subunit 41, and a thermal insulation subunit 43, wherein the high temperature heating subunit 42 and the low temperature heater
  • the central portion of the unit 41 and the insulating subunit 43 can form a reaction hole position for insertion
  • the reaction tube 5 the high temperature heating subunit 42 is located below the low temperature heating subunit 41, and the thermal insulation subunit 43 is located between the high temperature heating subunit 42 and the low temperature heating subunit 41.
  • the heat insulating sub-unit 43 is for preventing the low-temperature heating sub-unit 41 from absorbing the radiant heat of the high-temperature heating sub-unit 42.
  • the lower portion and the upper portion of the reaction tube 5 are respectively heated by the high temperature heating subunit 42 and the low temperature heating subunit 41, on the one hand, the temperature environment required for the amplification reaction is ensured, and on the other hand, the environment is effectively overcome.
  • the effect of temperature fluctuations on the amplification reaction ensures the efficiency of the amplification reaction.
  • the lower machine control subsystem 2 includes two temperature control loops for respectively controlling the reaction temperatures of the high temperature heating subunit 42 and the low temperature heating subunit 41 of the heating module 4.
  • the reaction hole position is formed in the central portion of the high temperature heating subunit 42, the low temperature heating subunit 41, and the heat insulating subunit 43, and the heating of the lower portion and the upper portion of the reaction tube 5 can be caused by the high temperature heating subunit 42 and the low temperature heating subunit 41, respectively. Evenly. Of course, in other embodiments, the reaction hole position may also be formed at a position biased to the center of the high temperature heating subunit 42 and the low temperature heating subunit 41.
  • the middle portion of the heat insulating sub-unit 43 includes a through hole to form a reaction hole position, so that the reaction tube 5 can smoothly enter the high temperature heating subunit 42 and the low temperature heating subunit 41, and the heat insulating subunit 43 heats the radiant heat of the high temperature subunit 42. Export to the side and then radiate to the environment via an external heat sink.
  • the specific structure of the high temperature heating subunit 42 and the low temperature heating subunit 41 may be that the high temperature heating subunit 42 includes a lower layer heating rubber 421 and a lower layer heat conducting module 423, and the lower layer heating rubber 421 is located at a side of the lower layer heat conducting module 423.
  • the lower heat conduction module 423 can transfer heat generated by the lower layer heating rubber 421 to a lower portion of the reaction tube 5;
  • the low temperature heating subunit 41 includes an upper layer heating rubber 411 and an upper layer heat conducting module 413.
  • the upper layer heating rubber 411 is located at a side of the upper layer heat conducting module 413, and the upper layer heat conducting module 413 can generate the upper layer heating rubber 411. Heat is transferred to the upper portion of the reaction tube 5.
  • the upper heating rubber 411 is located on the side of the upper heat conducting module 413, and the lower heating rubber 421 is located on the side of the lower heat conducting module 423.
  • the side heating is used to improve the high temperature heating subunit 42 and the low temperature heating subunit 41.
  • Temperature uniformity can reduce the heat load of the high temperature heating subunit 42 and the low temperature heating subunit 41 itself; the thermal insulation subunit 43 can The effect of the high temperature heating subunit 42 on the low temperature heating subunit 41 is effectively overcome, ensuring isothermal amplification efficiency.
  • a fiber fixing hole 414 may be disposed on the upper heat conducting module for fixing the excitation fiber 32 and the receiving fiber 33.
  • the high temperature heating subunit 42 further includes a lower layer temperature sensor 422 connected to the lower computer control subsystem 2 for converting the measured heating temperature of the high temperature heating subunit 42 Is an electrical signal and feedback to the lower computer control subsystem 2 in real time;
  • the low temperature heating subunit 41 further includes an upper layer temperature measuring sensor 412 connected to the lower computer control subsystem 2 for converting the measured heating temperature of the low temperature heating subunit 41 into an electrical signal and feeding back to the station in real time. Describe the lower machine control subsystem 2;
  • the lower computer control subsystem 2 is capable of receiving temperature signals of the lower temperature sensor 422 and the upper temperature sensor 412, and inputting the input received by the host computer interaction subsystem 1 according to the temperature signal.
  • the difference between the set temperatures of the commands is used to adjust the heating temperature of the heating module 4.
  • the lower computer control subsystem 2 can adjust the temperature control signal of the heating module 4 according to the difference to achieve a suitable heating temperature.
  • the temperature of the reaction tube 5 is maintained in an appropriate range.
  • the lower computer control subsystem 2 adjusts the output to the high temperature heating subunit 42 and according to the built-in control algorithm according to the difference between the actual temperature detected by the lower temperature sensor 422 and the upper temperature sensor 412 and the initial set temperature.
  • the driving signal amplitude of the low temperature heating sub-unit 41 realizes dual-loop closed-loop temperature control.
  • the high temperature heating subunit 42 and the low temperature heating subunit 41 respectively comprise 8 mutually corresponding upper and lower reaction holes, and the two cooperate with each other, allowing 8 reaction tubes 5 to simultaneously perform convection PCR isothermal. Amplification.
  • the fluorescent dye in the reaction tube 5 includes two types, respectively corresponding to two wavelengths, one excitation light source 311 is passed through the forward optical unit 312 composed of the excitation filter and the lens, and then transmitted to the two reaction tubes 5 via the excitation fiber 32. .
  • one excitation light source 311 is passed through the forward optical unit 312 composed of the excitation filter and the lens, and then transmitted to the two reaction tubes 5 via the excitation fiber 32.
  • a group of 4 wavelength LEDs is formed (group a)
  • another group of 4 other wavelengths is used to form another group (group b)
  • the light emitting diodes and their corresponding forward optical units 312 form an excitation module set.
  • the same wavelength fluorescent signals from the four reaction tubes 5 are respectively collected by four independent receiving fibers 33, and then passed through a focusing optical lens 341 composed of a focusing lens and a receiving filter.
  • the same photodiode is divided into two groups (group A, group B), each group corresponding to one fluorescence wavelength.
  • the excitation subunit 31 and the reception subunit 32 are controlled by the logic of the lower computer control subsystem 2, according to a certain time division multiplexing principle, at a certain moment, only for a single reaction tube 5, or non-interference with each other
  • a plurality of reaction tubes 5 are subjected to dual wavelength detection.
  • the detection mechanism for the polymerase chain reaction and the polymerase chain reaction device of the present invention can be seen by the description of various embodiments of the detection mechanism for polymerase chain reaction and the polymerase chain reaction device of the present invention.
  • the embodiment supports multi-wavelength fluorescent dyes, has the characteristics of simple structure, short detection time, low cost, small size, and supports the working mode of on-going inspection, and is a kind of nucleic acid diagnosis with high flexibility, wide applicability and high efficiency. And analysis device.
  • the detection mechanism for polymerase chain reaction and the polymerase chain reaction device embodiment of the invention can realize convective polymerase chain reaction, and convection PCR relies on single or two constant temperatures as reaction heat sources compared with common PCR technology.
  • the complexity of the gene amplification device is significantly reduced; at the same time, the periodic thermal cycle required for PCR amplification is realized by the thermal convection of the reaction sample in the reaction tube, and the thermal cycle time is significantly smaller than the ordinary PCR thermal cycle. Time, therefore, convection PCR can often be completed in 20-30 minutes.
  • convective PCR based on isothermal reaction conditions can significantly reduce device complexity and detection cost, and shorten detection time.
  • Real-time convection PCR amplification can detect the fluorescence signal in the sample amplification process in real time, discriminate the negative/positive of the detection sample, and even realize semi-quantitative/quantitative detection.
  • Real-time convection PCR amplification omits all kinds of subsequent detection steps for nucleic acid amplification products, such as electrophoresis detection, which is beneficial to overcome false positives caused by aerosol contamination, and on the other hand, further shortens the detection time in nucleic acid-based diagnostics.
  • the field of rapid disease detection has good development and application prospects.

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Abstract

一种用于聚合酶链式反应的检测机构（3）及聚合酶链式反应装置，其中检测机构（3）包括至少一个激发模块组，每个激发模块组包括两个激发模块（31），激发模块组能够提供两种波长的激发光；激发光纤（32），与激发模块组连接，激发光纤（32）能够将激发光传输到至少一个反应试管（5），每个反应试管（5）均接收两种波长的激发光；接收光纤（33），能够收集并传输反应试管（5）的荧光信号；至少一个接收模块组，与接收光纤（33）连接，每个接收模块组包括两个接收模块（34），以分别接收来自同一个反应试管（5）的两种波长的荧光信号，并将荧光信号转换为电信号输出；检测机构（3）分时地对所述反应试管（5）进行检测，并复用所述接收模块组获得输出结果。

Description

用于聚合酶链式反应的检测机构及聚合酶链式反应装置 技术领域
本发明涉及生物医学工程技术领域，尤其涉及一种用于聚合酶链式反应的检测机构及聚合酶链式反应装置。
背景技术
聚合酶链式反应(Polymerase Chain Reaction，PCR)是一种分子生物学技术，用于扩增特定的DNA片段。聚合酶链式反应一般需要对反应混合物，在2个或3个温度之间，进行重复的热循环步骤。
作为分子生物学中最重要的技术手段之一，PCR技术自诞生到现在，在生命医学领域发挥了巨大的作用。PCR技术具有灵敏度高、特异性好的特点，尤其是荧光定量PCR技术能够对检测样品的原始浓度进行定量，为疾病诊断提供重要的临床检验信息。PCR为一种周期性的基因扩增反应，每个扩增周期包括DNA变性、退火及延伸三个阶段，且每个阶段需要不同的温度条件，三个阶段构成一个完整的热循环周期。PCR所需的周期性反应温度条件往往由专业的PCR基因扩增仪来提供。PCR基因扩增仪通过复杂的软硬件设计来提供，并实时切换PCR所需的三个反应温度。在不同反应温度间的相互切换过程中，受仪器升降温速率的限制，不同反应阶段间的过渡过程往往需要较长时间，这使得PCR反应时间平均达到了1.5～2.5个小时。
作为一种新型PCR扩增技术，对流PCR依靠一个或者二个恒定的反应温度，在反应试管两端建立了稳定的温度梯度，基于热流体动力学原理，反应试管内产生了周期性运动流场，使得扩增样品在温度不同的试管两端间往复运动，由此获得了PCR扩增所需的温度条件。
但目前，现有的对流PCR反应装置还存在诸多不足，如不能对样品扩增过程中的荧光信号实现多波长实时检测，不能支持随到随检操作模式，这严重影响了对检测时间的控制，使得PCR扩增技术的总耗时始终无法降低到理想范围； 其次，控温方式单一，扩增反应易受外界环境温度的影响，而且检测过程灵活度较低；另外，检测设备的器件繁多，结构复杂，检测成本高。
发明内容
本发明的目的是提出一种用于聚合酶链式反应的检测机构及聚合酶链式反应装置，以实现聚合酶链式反应，并对扩增反应中的荧光信号进行实时检测。
为实现上述目的，本发明提供了一种用于聚合酶链式反应的检测机构，包括：
至少一个激发模块组，每个所述激发模块组包括两个激发模块，所述激发模块组能够提供两种波长的激发光；
激发光纤，与所述激发模块组连接，所述激发光纤能够将所述激发光传输到至少一个反应试管，每个所述反应试管均接收两种波长的激发光；
接收光纤，能够收集并传输所述反应试管的荧光信号；
至少一个接收模块组，与所述接收光纤连接，每个所述接收模块组包括两个接收模块，以分别接收来自同一个所述反应试管的两种波长的所述荧光信号，并将所述荧光信号转换为电信号输出；
所述检测机构分时地对所述反应试管进行检测，并复用所述接收模块组获得输出结果。
进一步地，每个所述激发模块均包括激发光源和前向光学单元，所述激发光源经由所述前向光学单元向所述激发光纤传输所述激发光，每个所述激发光源能够提供一种波长的激发光，并通过所述激发光纤分别传输至所述反应试管。
进一步地，所述前向光学单元包括透镜和激发滤光片，所述透镜位于靠近所述激发光源的一侧。
进一步地，每个所述接收模块均包括后向光学单元和光电传感器，所述后向光学单元用于将所述荧光信号传输至所述光电传感器，所述光电传感器用于将所述荧光信号转换为电信号输出。
进一步地，所述后向光学单元包括聚焦透镜和接收滤光片，所述聚焦透镜位于靠近所述接收光纤的一侧。
进一步地，所述激发光纤与其相对应的所述接收光纤之间互成90度光学角度。
为实现上述目的，本发明还提供了一种聚合酶链式反应装置，包括上述的用于聚合酶链式反应的检测机构。
进一步地，还包括上位机人机交互子系统、下位机控制子系统、加热模块和遮光模块，其中：
所述上位机人机交互子系统与所述下位机控制子系统数据连接，所述上位机人机交互子系统用于提供人机交互界面，并接收操作人员的输入指令；
所述下位机控制子系统用于根据所述上位机人机交互子系统所接收的输入指令，控制所述加热模块的温度；
所述加热模块能够为实现对流式聚合酶链式反应提供相应的加热温度；
所述遮光模块用于遮挡进入所述反应试管的光线。
进一步地，所述遮光模块包括上遮光盖与下遮光门，所述上遮光盖用于遮挡外界可见光，所述下遮光门包括弹性件，所述弹性件能够使得所述下遮光门在正常情况下为关闭状态；在所述反应试管插入反应孔位的过程中，所述下遮光门能够阻挡可见光进入所述反应试管。
进一步地，所述加热模块包括高温加热子单元、低温加热子单元和隔热子单元，其中所述高温加热子单元、所述低温加热子单元和所述隔热子单元的中心部分能够形成反应孔位，以插入所述反应试管，所述高温加热子单元位于所述低温加热子单元的下方，所述隔热子单元位于所述高温加热子单元和所述低温加热子单元之间，用于防止所述低温加热子单元吸收所述高温加热子单元的辐射热量。
进一步地，所述高温加热子单元包括下层加热橡胶、下层导热模块，所述下层加热橡胶位于所述下层导热模块的侧面，所述下层导热模块能够将所述下层加热橡胶产生的热量传递至所述反应试管的下部；
所述低温加热子单元包括上层加热橡胶、上层导热模块，所述上层加热橡胶位于所述上层导热模块的侧面，所述上层导热模块能够将所述上层加热橡胶产生的热量传递至所述反应试管的上部。
进一步地，所述高温加热子单元还包括与所述下位机控制子系统连接的下层测温传感器，用于将测量的所述高温加热子单元的加热温度转换为电信号并实时反馈给所述下位机控制子系统；
所述低温加热子单元还包括与所述下位机控制子系统连接的上层测温传感器，用于将测量的所述低温加热子单元的加热温度转换为电信号并实时反馈给所述下位机控制子系统；
所述下位机控制子系统能够接收所述下层测温传感器和所述上层测温传感器的温度信号，并根据所述温度信号与所述上位机人机交互子系统所接收的输入指令所设定温度之间的差值调整所述加热模块的加热温度。
基于上述技术方案，本发明的检测机构设有至少一个激发模块组，每个激发模块组包括两个激发模块，这至少两个激发模块能够提供两种波长的激发光，激发光纤将两种波长的激发光传输到对应的反应试管，每个反应试管均接收两种波长的激发光，反应试管中的荧光染料被激发光照射之后发出荧光信号，然后经接收光纤传输至至少一个接收模块组，每个接收模块组接收来自于同一个反应试管的两种波长的荧光信号，并将其转化为电信号输出。
该检测机构可以采用双波长检测，不论激发模块和反应试管的个数为多少，均可通过分时复用的原则，利用至少一个接收模块组即可完成对多个反应试管的同时检测。当反应试管为两个及以上时，分时是指对两个及以上反应试管进行分时检测；复用是指多个反应试管在不同时刻可以共用接收模块组，这样可实现对接收模块组的重复利用，显著减少了检测模块的器件数量，降低了模块的复杂度和成本；共用接收模块还有利于确保检测结果的一致性；另外，该检测机构可允许多个反应试管循环检测，实现对荧光信号的实时检测，随到随检，缩短了检测时间。
附图说明
图1为本发明用于聚合酶链式反应的检测机构一个实施例的结构示意图。
图2为本发明聚合酶链式反应装置一个实施例的结构示意图。
图3为本发明聚合酶链式反应装置一个实施例中一个独立反应孔位的结构 示意图。
图4为本发明聚合酶链式反应装置一个实施例中加热模块的结构示意图。
图中：
1-上位机人机交互子系统，2-下位机控制子系统，3-检测机构，31-激发模块，311-激发光源，312-前向光学单元，32-激发光纤，33-接收光纤，34-接收模块，341-后向光学单元，342-光电传感器，4-加热模块，41-低温加热子单元，42-高温加热子单元，43-隔热子单元，411-上层加热橡胶，412-上层测温传感器，413-上层导热模块，414-光纤固定孔，421-下层加热橡胶，422-下层测温传感器，423-下层导热模块，5-反应试管，6-遮光模块，61-上遮光盖，62-下遮光门。
具体实施方式
下面通过附图和实施例，对本发明的技术方案做进一步的详细描述。
在本发明的描述中，需要理解的是，术语“中心”、“横向”、“纵向”、“前”、“后”、“左”、“右”、“上”、“下”、“竖直”、“水平”、“顶”、“底”、“内”、“外”等指示的方位或位置关系为基于附图所示的方位或位置关系，仅是为了便于描述本发明和简化描述，而不是指示或暗示所指的装置或元件必须具有特定的方位、以特定的方位构造和操作，因此不能理解为对本发明保护范围的限制。
如图1所示，为本发明用于聚合酶链式反应的检测机构一个实施例的结构示意图。该用于聚合酶链式反应的检测机构3包括：
至少一个激发模块组，每个所述激发模块组包括两个激发模块31，所述激发模块组能够提供两种波长的激发光；
激发光纤32，与所述激发模块组连接，所述激发光纤32能够将所述激发光传输到至少一个反应试管5，每个所述反应试管5均接收两种波长的激发光；
接收光纤33，能够收集并传输所述反应试管5的荧光信号；
至少一个接收模块组，与所述接收光纤33连接，每个所述接收模块组包括两个接收模块34，以分别接收来自同一个所述反应试管5的两种波长的所述荧光信号，并将所述荧光信号转换为电信号输出；
所述检测机构3分时地对所述反应试管进行检测，并复用所述接收模块组 获得输出结果。
上述检测机构设有至少一个激发模块组，每个激发模块组包括两个激发模块，这至少两个激发模块能够提供两种波长的激发光，激发光纤将两种波长的激发光传输到对应的反应试管，每个反应试管均接收两种波长的激发光，反应试管中的荧光染料被激发光照射之后发出荧光信号，然后经接收光纤传输至至少一个接收模块组，每个接收模块组接收来自于同一个反应试管的两种波长的荧光信号，并将其转化为电信号输出。
该检测机构可以采用双波长检测，不论激发模块和反应试管的个数为多少，均可通过分时复用的原则，利用至少一个接收模块组即可完成对多个反应试管的同时检测。当反应试管为两个及以上时，分时是指对两个及以上反应试管进行分时检测；复用是指多个反应试管在不同时刻可以共用接收模块组，这样可实现对接收模块组的重复利用，显著减少了检测模块的器件数量，降低了模块的复杂度和成本；共用接收模块还有利于确保检测结果的一致性；另外，该检测机构可允许多个反应试管循环检测，实现对荧光信号的实时检测，随到随检，缩短了检测时间。
另外，当激发模块组包括两个及以上时，每个激发模块组所提供的两种波长的激发光可以不同，即可以有两种或两种以上的波长，从而实现对同一个反应孔位上的反应试管实施多波长检测。
激发模块31的具体实现形式有多种选择，在一个优选的实施例中，每个所述激发模块31均包括激发光源311和前向光学单元312，所述激发光源311经由所述前向光学单元312向所述激发光纤32传输所述激发光，每个所述激发光源311能够提供一种波长的激发光，并通过所述激发光纤32分别传输至所述反应试管5。
其中，所述激发光源311可以选为发光二极管(LED光源)，其体积小、电压低、使用寿命长，且成本低廉。由多个LED光源构成激发光整列，整列中的LED光源允许具有多个不同波长，由多根并行分布的激发光纤32分别传递至多个反应试管5的反应孔位。
另外，所述前向光学单元312可以包括透镜和激发滤光片，所述透镜位于 靠近所述激发光源311的一侧，即相比于所述激发滤光片来说，所述透镜更靠近所述激发光源311。其中透镜具有聚光的作用，激发滤光片能够选择特定波长的激发光。
接收模块的具体实现形式也可以有较为灵活的选择，在一个优选的实施例中，每个所述接收模块34均包括后向光学单元341和光电传感器342，所述后向光学单元341用于将所述荧光信号传输至所述光电传感器342，所述光电传感器342用于将所述荧光信号转换为电信号输出。
其中，所述光电传感器342可以为光电二极管，其线性好、灵敏度高，噪声较低，价格低廉，体积小巧，且使用寿命长。多个光电二极管可构成光电传感器整列，通过多根并行分布的接收光纤33接收来自多个反应孔位的荧光信号，然后将采集到的荧光信号转化为电信号并传送给下位机控制子系统2，由其进行下一步的信号及数据处理。
另外，所述后向光学单元341包括聚焦透镜和接收滤光片，所述聚焦透镜位于靠近所述接收光纤33的一侧，即相对于接收滤光片来说，聚焦透镜更靠近接收光纤33，以通过聚焦透镜实现更好的接收效果。
为了获取最优的灵敏度与信噪比，所述激发光纤32与其相对应的所述接收光纤33之间互成90度光学角度。当然，在其他实施例中，所述激发光纤32与其相对应的所述接收光纤33之间也可以互成其他角度。
如图2所示，本发明还提出一种聚合酶链式反应装置，包括上述各实施例中所述的用于聚合酶链式反应的检测机构3。
在一个实施例中，聚合酶链式反应装置还可以包括上位机人机交互子系统1、下位机控制子系统2、加热模块4和遮光模块6，其中：
所述上位机人机交互子系统1与所述下位机控制子系统2数据连接，即所述上位机人机交互子系统1与所述下位机控制子系统2相互连接并实现数据交换，所述上位机人机交互子系统1用于提供人机交互界面，并接收操作人员的输入指令，还可以对数据进行分析和处理；
所述下位机控制子系统2用于根据所述上位机人机交互子系统1所接收的输入指令，控制所述加热模块4的温度；
所述加热模块4能够为实现对流式聚合酶链式反应提供相应的加热温度；
所述遮光模块6用于遮挡进入所述反应试管5的光线，此处的光线主要是指外界环境中的光线。
其中，上位机人机交互子系统1可以设置独立处理器和触控屏，一方面提供了友好的人机交互操作界面并根据用户输入指令控制下位机控制子系统2的运行，另一方面还可对检测结果及数据文件进行分析与管理；下位机控制子系统2用于控制加热模块4的温度，为CPCR(对流式聚合酶链式反应)等温扩增提供稳定的反应温度；上位机人机交互子系统1与下位机控制子系统2之间可以通过串行接口或者USB接口进行数据通信。检测机构3与下位机控制子系统2相配合，实现CPCR等温扩增过程中，荧光检测信号的实时采集。
下位机控制子系统2除了能够输出控制信号给加热模块4，确保期望的反应温度，还可以与检测机构相互配合，实现多波长荧光检测。
另外，遮光模块6可以针对每个检测孔位配置独立的遮光子单元，克服检测孔位间的相互影响，既支持批量检测，也支持随到随检。如图3所示，所述遮光模块6包括上遮光盖61与下遮光门62，所述上遮光盖61用于遮挡外界环境中的可见光，所述下遮光门62包括弹性件，所述弹性件能够使得所述下遮光门62在正常情况下为关闭状态；在所述反应试管5插入反应孔位的过程中，所述下遮光门62能够阻挡可见光进入所述反应试管5。
上遮光盖61可以遮挡来自装置外部环境的可见光。下遮光门62包括弹性件，即下遮光门62为一个弹簧门，由于受弹簧力拉扯作用，除非插入反应试管5，该下遮光门62始终处于关闭状态，因此，它能够阻止仪器内部的可见光进入检测孔位，更为重要的是，在上遮光盖61打开后，插入反应试管5前或者插入过程中，下遮光门62能够遮挡可能进入检测孔位的可见光，这有效克服了随到随检工作模式下，检测孔位之间的相互干扰与影响。
为实现对流式聚合酶链式反应，加热模块4需要提供对流式扩增所需的反应温度条件。在一个实施例中，如图4所示，所述加热模块4包括高温加热子单元42、低温加热子单元41和隔热子单元43，其中所述高温加热子单元42、所述低温加热子单元41和所述隔热子单元43的中心部分能够形成反应孔位，以插入 所述反应试管5，所述高温加热子单元42位于所述低温加热子单元41的下方，所述隔热子单元43位于所述高温加热子单元42和所述低温加热子单元41之间，所述隔热子单元43用于防止所述低温加热子单元41吸收所述高温加热子单元42的辐射热量。
在加热模块4中，通过高温加热子单元42与低温加热子单元41分别对反应试管5的下部与上部进行加热，一方面确保了扩增反应所需的温度环境，另一方面有效克服了环境温度的波动可能对扩增反应带来的影响，确保了扩增反应效率。
其中，下位机控制子系统2中包括两个温度控制回路，分别控制加热模块4的高温加热子单元42与低温加热子单元41的反应温度。
反应孔位在高温加热子单元42、低温加热子单元41和隔热子单元43的中心部分形成，可以使得高温加热子单元42和低温加热子单元41分别对反应试管5下部和上部的加热比较均匀。当然，在其他实施例中，也可以在偏于高温加热子单元42和低温加热子单元41中心的位置形成该反应孔位。
隔热子单元43的中部包括一个通孔，形成反应孔位，使得反应试管5能够顺利进入高温加热子单元42和低温加热子单元41，隔热子单元43将高温加热子单元42的辐射热量导出到侧面，再经外部散热片散发到环境中。
高温加热子单元42和低温加热子单元41的具体结构可以为：所述高温加热子单元42包括下层加热橡胶421、下层导热模块423，所述下层加热橡胶421位于所述下层导热模块423的侧面，所述下层导热模块423能够将所述下层加热橡胶421产生的热量传递至所述反应试管5的下部；
所述低温加热子单元41包括上层加热橡胶411、上层导热模块413，所述上层加热橡胶411位于所述上层导热模块413的侧面，所述上层导热模块413能够将所述上层加热橡胶411产生的热量传递至所述反应试管5的上部。
加热模块4中，上层加热橡胶411位于上层导热模块413的侧面，下层加热橡胶421位于下层导热模块423的侧面，采用侧面加热的方式，一方面可以改善高温加热子单元42与低温加热子单元41的温度均匀性，另一方面可以可以降低高温加热子单元42和低温加热子单元41自身的热负载；隔热子单元43可以 有效地克服高温加热子单元42对低温加热子单元41的影响，确保了等温扩增效率。
另外，上层导热模块上可以设置光纤固定孔414，用于固定激发光纤32和接收光纤33。
为了实现有效的控温度制，所述高温加热子单元42还包括与所述下位机控制子系统2连接的下层测温传感器422，用于将测量的所述高温加热子单元42的加热温度转换为电信号并实时反馈给所述下位机控制子系统2；
所述低温加热子单元41还包括与所述下位机控制子系统2连接的上层测温传感器412，用于将测量的所述低温加热子单元41的加热温度转换为电信号并实时反馈给所述下位机控制子系统2；
所述下位机控制子系统2能够接收所述下层测温传感器422和所述上层测温传感器412的温度信号，并根据所述温度信号与所述上位机人机交互子系统1所接收的输入指令所设定温度之间的差值调整所述加热模块4的加热温度，具体地，下位机控制子系统2可以根据该差值调整加热模块4的温度控制信号，以达到合适的加热温度，使反应试管5的温度维持在适当的范围。
下位机控制子系统2根据下层测温传感器422和上层测温传感器412所检测的实际温度与初始设定温度之间的差值，按照内置的控制算法，分别调整输出给高温加热子单元42和低温加热子单元41的驱动信号幅值，实现双回路闭环温度控制。
下面对本发明用于聚合酶链式反应的检测机构及聚合酶链式反应装置的一个实施例的结构原理进行说明：
以8个反应孔位数为例，高温加热子单元42与低温加热子单元41分别包括8个相互对应的上下层反应孔位，两者相互配合，允许8个反应试管5同时进行对流PCR等温扩增。
反应试管5内的荧光染料包括两类，分别对应2个波长，1个激发光源311经由激发滤光片和透镜构成的前向光学单元312后，再经激发光纤32传输到2个反应试管5。为了实现对8个孔位的双波长检测，由4个一种波长发光二极管构成一组(a组)，由4个另一种波长发光二极管构成另一组(b组)，共8个 发光二极管及其对应的前向光学单元312构成了激发模块组。
为了减少光电传感器的数量，将来自4个反应试管5的相同波长荧光信号分别由4根独立的接收光纤33收集，再经由聚焦透镜和接收滤光片构成的后向光学单元341后，进入到同一个光电二极管。4个光电二极管(PD1、PD2、PD3、PD4)均分为两组(A组、B组)，每组对应一个荧光波长。
荧光检测过程中，激发子单元31与接收子单元32受下位机控制子系统2的逻辑控制，按照一定的分时复用原则，在某一个时刻，仅对单个反应试管5，或者互不干涉的多个反应试管5进行双波长检测。通过让多个反应试管5之间共享激发光源与光电二极管传感器，显著减少了荧光检测机构的器件数量，降低了模块复杂度与成本，同时，共用检测传感器有利于确保检测结果的一致性。
通过对本发明用于聚合酶链式反应的检测机构及聚合酶链式反应装置的多个实施例的说明，可以看到本发明用于聚合酶链式反应的检测机构及聚合酶链式反应装置实施例支持多种波长荧光染料，具有结构简单、检测时间短、成本低廉、体积小巧的特点，支持随到随检的工作模式，为一种灵活度高、适用性广、高效率的核酸诊断与分析装置。
本发明用于聚合酶链式反应的检测机构及聚合酶链式反应装置实施例能够实现对流式聚合酶链式反应，与普通PCR技术相比，对流PCR依靠单一或者两个恒定温度作为反应热源，显著降低了基因扩增装置的复杂度；同时，PCR扩增所需的周期性热循环通过反应样品在反应试管内的热对流来实现，其热循环周期时间要显著小于普通PCR热循环周期时间，因此，对流PCR往往能够在20-30分钟内完成。
与普通PCR相比，基于等温反应条件的对流PCR能够显著降低装置复杂度与检测成本，缩短检测时间。实时对流PCR扩增能够对样品扩增过程中的荧光信号进行实时检测，判别检测样品的阴/阳性，甚至还可以实现半定量/定量检测。实时对流PCR扩增省略了电泳检测等各类对核酸扩增产物的后续检测步骤，一方面有利于克服气溶胶污染导致的假阳性，另一方面也进一步缩短了检测时间，在基于核酸诊断的疾病快速检测领域具有良好的发展与应用前景。
以上所述仅是本发明的优选实施方式，应当指出，对于本技术领域的普通 技术人员来说，在不脱离本发明原理的前提下，还可以做出若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。

Claims (12)

  1. 一种用于聚合酶链式反应的检测机构(3)，其特征在于，包括：
    至少一个激发模块组，每个所述激发模块组包括两个激发模块(31)，所述激发模块组能够提供两种波长的激发光；
    激发光纤(32)，与所述激发模块组连接，所述激发光纤(32)能够将所述激发光传输到至少一个反应试管(5)，每个所述反应试管(5)均接收两种波长的激发光；
    接收光纤(33)，能够收集并传输所述反应试管(5)的荧光信号；
    至少一个接收模块组，与所述接收光纤(33)连接，每个所述接收模块组包括两个接收模块(34)，以分别接收来自同一个所述反应试管(5)的两种波长的所述荧光信号，并将所述荧光信号转换为电信号输出；
    所述检测机构(3)分时地对所述反应试管进行检测，并复用所述接收模块组获得输出结果。
  2. 根据权利要求1所述的用于聚合酶链式反应的检测机构(3)，其特征在于，每个所述激发模块(31)均包括激发光源(311)和前向光学单元(312)，所述激发光源(311)经由所述前向光学单元(312)向所述激发光纤(32)传输所述激发光，每个所述激发光源(311)能够提供一种波长的激发光，并通过所述激发光纤(32)分别传输至所述反应试管(5)。
  3. 根据权利要求2所述的用于聚合酶链式反应的检测机构(3)，其特征在于，所述前向光学单元(312)包括透镜和激发滤光片，所述透镜位于靠近所述激发光源(311)的一侧。
  4. 根据权利要求1所述的用于聚合酶链式反应的检测机构(3)，其特征在于，每个所述接收模块(34)均包括后向光学单元(341)和光电传感器(342)，所述后向光学单元(341)用于将所述荧光信号传输至所述光电传感器(342)，所述光电传感器(342)用于将所述荧光信号转换为电信号输出。
  5. 根据权利要求4所述的用于聚合酶链式反应的检测机构(3)，其特征在于，所述后向光学单元(341)包括聚焦透镜和接收滤光片，所述聚焦透镜位于靠近 所述接收光纤(33)的一侧。
  6. 根据权利要求1所述的用于聚合酶链式反应的检测机构(3)，其特征在于，所述激发光纤(32)与其相对应的所述接收光纤(33)之间互成90度光学角度。
  7. 一种聚合酶链式反应装置，其特征在于，包括如权利要求1～6任一项所述的用于聚合酶链式反应的检测机构(3)。
  8. 根据权利要求7所述的聚合酶链式反应装置，其特征在于，还包括上位机人机交互子系统(1)、下位机控制子系统(2)、加热模块(4)和遮光模块(6)，其中：
    所述上位机人机交互子系统(1)与所述下位机控制子系统(2)数据连接，所述上位机人机交互子系统(1)用于提供人机交互界面，并接收操作人员的输入指令；
    所述下位机控制子系统(2)用于根据所述上位机人机交互子系统(1)所接收的输入指令，控制所述加热模块(4)的温度；
    所述加热模块(4)能够为实现对流式聚合酶链式反应提供相应的加热温度；
    所述遮光模块(6)用于遮挡进入所述反应试管(5)的光线。
  9. 根据权利要求8所述的聚合酶链式反应装置，其特征在于，所述遮光模块(6)包括上遮光盖(61)与下遮光门(62)，所述上遮光盖(61)用于遮挡外界可见光，所述下遮光门(62)包括弹性件，所述弹性件能够使得所述下遮光门(62)在正常情况下为关闭状态；在所述反应试管(5)插入反应孔位的过程中，所述下遮光门(62)能够阻挡可见光进入所述反应试管(5)。
  10. 根据权利要求9所述的聚合酶链式反应装置，其特征在于，所述加热模块(4)包括高温加热子单元(42)、低温加热子单元(41)和隔热子单元(43)，其中所述高温加热子单元(42)、所述低温加热子单元(41)和所述隔热子单元(43)的中心部分能够形成反应孔位，以插入所述反应试管(5)，所述高温加热子单元(42)位于所述低温加热子单元(41)的下方，所述隔热子单元(43)位于所述高温加热子单元(42)和所述低温加热子单元(41)之间，用于防止所述低温加热子单元(41)吸收所述高温加热子单元(42)的辐射热量。
  11. 根据权利要求10所述的聚合酶链式反应装置，其特征在于，所述高温加热 子单元(42)包括下层加热橡胶(421)、下层导热模块(423)，所述下层加热橡胶(421)位于所述下层导热模块(423)的侧面，所述下层导热模块(423)能够将所述下层加热橡胶(421)产生的热量传递至所述反应试管(5)的下部；
    所述低温加热子单元(41)包括上层加热橡胶(411)、上层导热模块(413)，所述上层加热橡胶(411)位于所述上层导热模块(413)的侧面，所述上层导热模块(413)能够将所述上层加热橡胶(411)产生的热量传递至所述反应试管(5)的上部。
  12. 根据权利要求11所述的聚合酶链式反应装置，其特征在于，所述高温加热子单元(42)还包括与所述下位机控制子系统(2)连接的下层测温传感器(422)，用于将测量的所述高温加热子单元(42)的加热温度转换为电信号并实时反馈给所述下位机控制子系统(2)；
    所述低温加热子单元(41)还包括与所述下位机控制子系统(2)连接的上层测温传感器(412)，用于将测量的所述低温加热子单元(41)的加热温度转换为电信号并实时反馈给所述下位机控制子系统(2)；
    所述下位机控制子系统(2)能够接收所述下层测温传感器(422)和所述上层测温传感器(412)的温度信号，并根据所述温度信号与所述上位机人机交互子系统(1)所接收的输入指令所设定温度之间的差值调整所述加热模块(4)的加热温度。
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